Autoimmune diseases have long been regarded as illnesses in which the immune system creates autoantibodies to attack the body itself. But today, researchers at the California non-profit Autoimmunity Research Foundation (ARF) explain that the antibodies observed in autoimmune disease actually result from alteration of human genes and gene products by hidden bacteria.

Not long ago, scientists believed they had located all bacteria capable of causing human disease, But DNA discoveries in the last decade have led the NIH Human Microbiome Project to now estimate that as many as 90% of cells in the body are bacterial in origin. Many of these bacteria, which have yet to be named and characterized, have been implicated in the progression of autoimmune disease.

In a paper published in Autoimmunity Reviews, the ARF team, under the guidance of Professor Trevor Marshall of Murdoch University, Western Australia, has explained how Homo sapiens must now be viewed as a superorganism in which a plethora of bacterial genomes a metagenome work in concert with our own. Marshall and team contend that the human genome can no longer be studied in isolation.

"When analyzing a genetic pathway, we must study how bacterial and human genes interact, in order to fully understand any process related to the human superorganism," states Marshall. "Especially since some of these pathways contribute to the pathogenesis of autoimmune disease."

For example, the team notes that the single gene ACE has an impact on myocardial infarction, renal tubular dysgenesis, Alzheimer's, the progression of SARS, diabetes mellitus, and sarcoidosis, yet recently ACE has been shown to be affected by the common species Lactobacillus and Bifidobacteria. Found in yogurt, these species are often considered to be innocuous or "friendly."

"No one would argue that these species aren't present in the human body, yet there has been inadequate study of how these 'friendly' species affect disease," states Amy Proal, the paper's lead author.

"What we thought were autoantibodies generated against the body itself can now be understood as antibodies directed against the hidden bacteria," states Marshall. "In autoimmune disease, the immune system is not attacking itself. It is protecting the body from pathogens."

To validate their lab discoveries, Marshall's team has been conducting an observational clinical trial of more than 500 autoimmune patients and reported at the recent 6th International Congress on Autoimmunity that antibacterial therapies targeted at these hidden microbes are capable of reversing autoimmune disease processes.

Source: Autoimmunity Research, Inc

Autoimmun Rev. 2009 Feb 12.

Autoimmune disease in the era of the metagenome.Proal AD, Albert PJ, Marshall T.

Georgetown University.

Studies of autoimmune disease have focused on the characteristics of the identifiable antibodies. But as our knowledge of the genes associated with the disease states expands, we understand that humans must be viewed as superorganisms in which a plethora of bacterial genomes -- a metagenome - work in tandem with our own. The NIH has estimated that 90% of the cells in Homo sapiens are microbial and not human in origin. Some of these microbes create metabolites that interfere with the expression of genes associated with autoimmune disease. Thus, we must re-examine how human gene transcription is affected by the plethora of microbial metabolites. We can no longer assume that antibodies generated in autoimmune disease are created solely as autoantibodies to human DNA. Evidence is now emerging that the human microbiota accumulates during a lifetime, and a variety of persistence mechanisms are coming to light. In one model, obstruction of VDR nuclear-receptor-transcription prevents the innate immune system from making key antimicrobials, allowing the microbes to persist. Genes from these microbes must necessarily impact disease progression. Recent efforts to decrease this VDR-perverting microbiota in patients with autoimmune disease have resulted in reversal of autoimmune processes. As the NIH Human Microbiome Project continues to better characterize the human metagenome, new insights into autoimmune pathogenesis are beginning to emerge.

ArticleWith the discovery of T helper 17 (TH17) cells, the examination of the role of different TH-cell subsets in autoimmunity has been a topic of great interest. In this study, Hoyer et al. examined the contribution of the TH1-type cytokine interferon- (IFN) and the TH17-type cytokine interleukin-17 (IL-17) in the development of autoimmunity. Il2-/- mice (which develop spontaneous systemic autoimmune disease and die of haemolytic anaemia) had increased levels of IFN and IL-17 compared with wild-type mice. Mice that lacked both IL-2 and IFN had higher rates of survival than Il2-/- mice, and this was due to decreased production of autoantibodies and macrophage-mediated phagocytosis owing to a lack of IFN. However, these mice eventually died as a result of colonic inflammation, which was accompanied by increased levels of Il17 mRNA.

Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.

There are more than 80 identified autoimmune diseases [1]. Multiple factors are thought to contribute to the development of immune response to self, including genetics, age and environment. In particular, viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. Multiple arms of the immune system may be involved in autoimmune pathology. Antigens are taken up by antigenpresenting cells (APCs) such as dendritic cells (DCs) and processed into peptides which are loaded onto major histocompatibility complex (MHC) molecules for presentation to T cells via clonotypic T cell receptors (TCRs). Cytolytic T cells (Tc, activated by MHC Class I on APC) can directly lyse a target, while T helper cells (Th, activated by MHC class II) release cytokines that can have direct effects or can activate macrophages, monocytes and B cells. B cells themselves have surface receptors that can bind surface antigens. Upon receiving signals from Th cells, the B cell secretes antibodies specific for the antigens. Antibody may bind its specific target alone or may bind to and activate macrophages simultaneously via the Fc receptor.

There are multiple mechanisms by which host infection by a pathogen can lead to autoimmunity (Fig. 1). The pathogen may carry elements that are similar enough in amino acid sequence or structure to self-antigen that the pathogen acts as a self-?mimic?. Termed ?molecular mimicry?, T or B cells that are activated in response to the pathogen are also crossreactive to self and lead to direct damage and further activation of other arms of the immune system. The pathogenmay also lead to disease via epitope spreading. In this model the immune response to a persisting pathogen, or direct lysis by the persisting pathogen, causes damage to self-tissue. Antigens released from damaged tissue are taken up by APCs, and this initiates a self-specific immune response. ?Bystander activation? describes an indirect or non-specific activation of autoimmune cells caused by the inflammatory environment present during infection. A domino effect can occur, where the non-specific activation of one armof the immune system leads to the activation of other arms. Lastly, infection may lead autoimmunity through the processing and presentation of ?cryptic antigens?. In contrast to dominant antigenic determinants, subdominant cryptic antigens are normally invisible to the immune system. The inflammatory environment that arises after infection can induce increased protease production and differential processing of released self-epitopes by APCs.

In this review, we discuss the evidence available for the involvement of specific pathogens in the initiation or exacerbation of representative autoimmune diseases. As will be mentioned, there is evidence for the involvement of different arms of the immune systems by many mechanisms, in both human disease and in animal models.
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Borrelia burgdorfeii

In the United States, Lyme disease is caused by the tick-borne spirochete Borrelia burgdorfeii (Bb). Sixty per cent of untreated patients develop arthritis that can last for several years, mainly in large joints such as the knee [84]. These patients have high titres of Bb-specific antibodies, and Bb DNA can be detected in the joint fluid by PCR [85]. Treatment of these patients with antibiotics usually ameliorates the arthritis, which indicates that bystander inflammatory response to the spirochete is responsible for early Lyme arthritis [86].A subset of patients will progress from acute to chronic arthritis despite treatment with antibiotics and lack of detectable Bb DNA in synovial fluid [85?87]. Antibioticresistant Lyme arthritis is associated with the MHC class II alleles human leucocyte antigen (HLA)-DRB1*0401, *0101 and *0404, indicating that its mechanism is T cell-mediated and distinct from acute Lyme arthritis [88].

Cellular and humoral responses to outer surface protein A (OspA) of Bb develop in around 70% of patients with antibiotic-resistant Lyme arthritis, often at the beginning of prolonged arthritic episodes [89?92]. T cell and humoral responses to OspA, but not to other spirochete antigens, were found to correlate with the presence or severity of arthritis [92,93]. Specifically, antibiotic-resistant patients responded preferentially to the T cell epitope OspA165?173, and T cells responsive to this epitope were expanded in the joint fluid compared with peripheral blood in HLA-DRB1*0401-positive patients [89,94,95]. An initial computer algorithm search identified lymphocyte function-associated antigen (LFA)1aL332?340, a peptide derived from the light chain of human leucocyte adhesion molecule, as homologous to OspA165?173, and able to bind HLA-DRB1*0401 [96]. Synovial fluid mononuclear cells from patients with antibiotic-resistant arthritis produced IFN-g in response to both OspA165?173 and LFA1aL332?340, suggesting that mimicry between these two proteins may cause the inflammation associated with arthritis. LFA-1a has also been identified in the synovia of patients with antibiotic- resistant Lyme arthritis [97].

However, other studies showed that in treatment-resistant patients, LFA1aL332?340 was a weak agonist for OspA165?173- specific T cells and mainly induced the Th2-type cytokine IL-13 [98]. LFA1aL332?340 binds well to HLA-DRB*0401, but not to the more commonly associated allele HLADRB1* 0101 [99]. In addition, although cross-reactive T cells were identified in the majority of patients in one study, there was no correlation between T cell response to LFA1aL332?340 and clinical status [100]. These studies weaken the argument that LFA1aL332?340 cross-reactivity is important in the pathology of antibiotic-resistant Lyme arthritis. On the other hand, Maier et al. identified 15 other human and murine selfpeptides that could stimulate an OspA165?173-specific T cell hybridoma [101], so other peptides may prove to be more important in disease pathology.

There are several rodent models in which arthritis is induced upon infection with Bb [102?105]. In C3H mice, joints are infiltrated with neutrophils 10?14 days after infection and, at the peak of arthritis (3?5 weeks), synovial lesions show leucocyte infiltration with mononuclear cells [103]. C57BL/6-beige mice, which have impaired macrophage motility and chemotaxis, develop severe arthritis [106], whereas C57BL/6 mice develop minimal arthritis unless deficient in IL-10 and IL-6 [107,108]. These studies indicate that macrophage-derived anti-inflammatory cytokines protect these mice from severe joint inflammation. Transferring Bb-specific T cells alone in the absence of B cells will exacerbate and accelerate the onset of arthritis in C57/BL6-SCID mice [109]. Rodentmodels are helpful only in studying acute Lyme arthritis, as the arthritis resolves within a few weeks and is not antibiotic-resistant.

Neurological complications, including myelitis and peripheral neuropathy, can occur in 10?12% of untreated patients infected with Bb and can arise even after antibiotic treatment [110]. Patients with chronic neuroborreliosis have been reported to have antibodies reactive to nerve axons in their serum [111], as well as antibodies and T cells specific for myelin basic protein (MBP) in spinal fluid [112,113]. Patient serum that was reactive to axons and neuroblastoma cells was also cross-reactive with Bb flagellin [111,114]. Next, it was discovered that a mAb for flagellin was cross-reactive with human heat shock protein 60 and with neuroblastoma cell lines [115,116] and slowed neurite outgrowth in culture [117]. Antibody crossreactivity has also been described between human central nervous system (CNS) proteins and Bb OspA [118]. Several host neural peptides were identified as cross-reactive with Bb-specific T cells from CSF of a patient with chronic neuroborreliosis using peptide libraries and biometric data analysis [119]. However, studies such as those in nonhuman primates suggest that bystander inflammatory responses to the persistently infective pathogen may explain more clearly the CNS complications of this disease [120?122].

Multiple sclerosis

Multiple sclerosis (MS) is characterized by a loss of the myelin sheath surrounding axons in the CNS [201]. Demyelination is associated with elevated levels of CD4+ T cells specific for major myelin proteins, and the disease is generally thought to be autoimmune [202?204]. Although it is not known precisely what triggers the development of MS, it is well established that relapses or disease flares in patients diagnosed with the relapsing?remitting form of MS are often associated with exogenous infections, particular upper respiratory infections. In total, more than 24 viral agents have been linked to MS [205,206]. Most of the associations have been circumstantial, but some studies have found evidence of specific pathogens in human tissue. Antigens from herpesvirus type 6 were found in MS plaques but not from tissues from other neurological disorders [207]. Similarly, compared with CSF from patients with other neurological diseases, CSF from MS patients was shown to have higher levels of the bacteria Chlamydia pneumoniae [208]. In vitro studies have also provided evidence linking MS and infectious agents. MS patients have activated T cells specific for MBP [209?211]. Eight pathogen-derived peptides, including epitopes from HSV, adenovirus and human papillomavirus, were identified that are able to activate MBP-specific T cell clones derived from MS patients [212]. Significantly, these peptides were found to be presented most efficiently by subtypes of HLA-DR2 that are associated with susceptibility to MS. Despite the difficulty in linking MS to any one pathogen, the amount of epidemiological evidence reported over the years shows that environmental factors play a strong role in disease development, and suggests that a cumulative lifetime exposure to certain microorganisms can influence disease development [213?216]. In addition, a recent study showed that the degree of concordance for monozygotic twins (generally reported at 40% or less) was influenced by environmental factors [217].

There are numerous rodent models of demyelination which, although not identical to the human disease, are used to study MS. The major infectious models in mice are Theiler?s murine encephalomyelitis virus (TMEV), murine hepatitis virus (MHV) and Semliki Forest virus (SFV). Each has distinct immunopathological mechanisms and illustrate the various potential ways pathogens may induce MS. There are two strains of TMEV (TMEV-DA and TMEV-BeAn) which cause an initial acute grey matter disease followed by a chronic progressive demyelination in the white matter of the spinal chord known as TMEV-induced demyelinating disease (TMEV-IDD) [205,218,219].

Although the two strains induce slightly different diseases, the key characteristics of TMEV-IDD (abnormal gait and spastic hindlimb paralysis) remain the same. Intracerebral (i.c.) injection of virus leads to persistent CNS infection; the level of infectious virus is low during the chronic phase, but abundant amounts of viral RNA and viral antigen can be detected throughout the lifetime of the mouse [220?222]. The immune response is initiated by the presentation of persistent viral antigens by CNS-resident APCs to Th1-type CD4+ T cells, but reactivity to myelin does not appear until after the onset of clinical symptoms (30?35 days post-infection) [223?226]. Thus, TMEV-IDD is caused by epitope spreading from viral determinants to self-myelin determinants. Interestingly, in SJL mice, reactivity appears to multiple myelin peptides starting with the immunodominant epitope and spreading at later time-points to other subdominant myelin determinants in a hierarchical manner [226,227]. In contrast to TMEV, mice inoculated with neurotropic strains of MHV will have a single major symptomatic episode (ataxia, hindlimb paresis, paralysis) from which the majority will recover [228]. CNS infection results in an influx of immune cells that for the most part will clear the virus, although virus does persist in low amounts [229]. Demyelination begins about 1 week post-infection and peaks at week 3, after which lesion repair and remyelination generally occurs [230?232]. The exact mechanism of demyelination in this model is somewhat controversial, but appears to be bystander myelin destruction by the immune response recruited initially to the CNS to control viral infection.There is no evidence of self-specific immunity in the CNS of MHV-infected mice [233]. T and B-cell deficient RAG1-/- mice, which were resistant to demyelination, developed histological disease after adoptive transfer with splenoctyes from MHV-inoculated mice, which involved the recruitment of activated macrophages/microglia to sites of demyelination in the spinal cord [234]. Chemokine receptor knock-out mice (CCR5-/-) showed reduced demyelination that correlated with reducedmacrophage but not T cell infiltration into the CNS of MHV-infected mice [235]. CD4- deficient mice showed less severe disease than CD8-deficient mice [236,237]. Collectively, these studies suggest that macrophages are responsible primarily for myelin destruction in the MHV model, but that T cells are required to recruit macrophages into the CNS. Like MHV, SFV leads to a transient clinical disease [238,239]. The virus is, for the most part, cleared from the CNS by day 6 post-infection, while demyelination peaks at day 14 and then wanes [240,241]. Demyelination is not seen in nude or SCID mice, demonstrating that it is T cell-mediated [240,242]. In BALB/c mice it is thought that demyelination is due to cytolytic damage of virus-infected oligodendrocytes, although this has not been proved definitively. Depletion of CD8+ T cells virtually abolished lesions of demyelination, whereas depletion of CD4+ T cells did not have that effect [243]. Other studies in BALB/c mice have shown that Th1-type cytokines are involved in viral clearance but not demyelination [244,245]. In C57/Bl6 mice, molecular mimicry may also play a role in demyelination. Infected mice have MBP-reactive T cells [246], and antibodies reactive to MBP and myelin oligodendrocyte protein (MOG) [247]. Computer algorithms uncovered homology between an epitope in the SFV surface protein E2 and MOG18?32 [248]. Mice primed with either peptide develop paralytic symptoms with histopathology resembling that of mice infected with SFV. The authors of that study concluded that the cross- eactive antibody response was mainly responsible for the demyelinating lesions.

Summary and perspectives

The immune system has evolved checks and balances to prevent the destruction of host tissue. It is perhaps not surprising that a strong immune response to an invading pathogen could disrupt this regulation and lead to autoimmunity. As outlined above, there is significant evidence suggesting that different classes of pathogens (bacteria, viruses and parasites) are involved in triggering or propagating selfreactive immune responses. However, the evidence for a definitive link for infection-induced autoimmunity is stronger for certain diseases than for others.

The argument for infection-induced pathology is much stronger for diseases associated with one or two specific pathogens than for diseases with multiple causal associations. For example, the fact that infection with C. jejuni is a common antecedent to GBS makes a strong argument that this disease is infection-triggered. In contrast, for diseases such as TID and MS that have been associated with dozens of pathogens, but none in particular, much more needs to be done to make a convincing case. The most compelling proof would be the disappearance of symptoms with the clearance of the infection. This is the case in Lyme disease, where treatment with antibiotics alleviates acute arthritis.However, as outlined previously in this paper, there are many ways a pathogen can cause disease even after the infection has been cleared. In these cases, epidemiological studies showing that people infected with a particular agent have an increased incidence of these diseases compared with people never infected, while not wholly definitive, would certainly strengthen the infection-induced autoimmunity argument.

In human autoimmune diseases, where direct evidence for a role for a particular pathogen is weak, it is all the more important to have supporting animal models. The strongest support comes from animal models in which infection with the agent thought to induce disease in humans causes similar symptoms in animals, as exemplified by induction of heart disease in mice infected with T. cruzi and CVB and arthritis in mice infected with Bb. In other animal models, disease can be shown to be induced by priming with a pathogen-derived antigen, thus strengthening the argument for the involvement of that pathogen in the human disease. The ability to induce heart disease in rats primed with Streptococcal M protein is strong evidence that S. pyogenes causes heart disease in humans via molecular mimicry. Although the link between S. pyogenes infection and neurological disorders in humans is uncertain, at best, the fact that movement and behaviour disorders can be induced in mice primed with S. pyogenes homogenate also lends credibility to that theory. In cases where it is uncertain whether a disease pathology is actually autoimmune (such as uveitis and myocarditis following CVB infection), animal models have played a crucial role in elucidating the potential mechanisms of disease induction.

The heterogeneity of the human population, rather than the weakness of the data, may be in play in instances where the evidence linking infection and autoimmunity is tenuous or even conflicting. It is not difficult to imagine that some people may be more susceptible to developing autoimmune disease following a particular infection than others, or that mimic peptides derived from different infectious agents may be able to trigger a particular autoimmune disease depending on the ability of the infected individual to present various epitopes in the context of their various HLA molecules. Defining the genetic markers that predispose patients to different autoimmune diseases with a suspected infectious
trigger would be an important contribution to defining the underlying disease pathogenesis.

Abstract
Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages.

However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy to evade the immune system. M2 are particularly efficient at scavenging self tissues following injury through receptors like the mannose receptor and scavenger receptor-A.

Thus, M2 may increase autoimmune disease by presenting self tissue to T cells. M2 may also exacerbate immune complex (IC)-mediated pathology and fibrosis, a hallmark of autoimmune disease in women, due to the release of profibrotic factors such as interleukin-1β, transforming growth factor-β, fibronectin and matrix metalloproteinases. We have found that M2 comprise anywhere from 30% to 70% of the infiltrate during acute viral or experimental autoimmune myocarditis, and shifts in M2 populations correlate with increased IC deposition, fibrosis and chronic autoimmune pathology. Thus, women may be at an increased risk of M2-mediated autoimmunity due to estrogen's ability to increase Th2 responses.
Keywords: Autoimmunity; Complement; Cytokines; Infection; Macrophage

Abstract Inflammation has long been implicated as a contributor to pathogenesis in many CNS illnesses, including Lyme neuroborreliosis. Borrelia burgdorferi is the spirochete that causes Lyme disease and it is known to potently induce the production of inflammatory mediators in a variety of cells. In experiments where B. burgdorferi was co-cultured in vitro with primary microglia, we observed robust expression and release of IL-6 and IL-8, CCL2 (MCP-1), CCL3 (MIP-1?), CCL4 (MIP-1?) and CCL5 (RANTES), but we detected no induction of microglial apoptosis. In contrast, SH-SY5Y (SY) neuroblastoma cells co-cultured with B. burgdorferi expressed negligible amounts of inflammatory mediators and also remained resistant to apoptosis. When SY cells were co-cultured with microglia and B. burgdorferi, significant neuronal apoptosis consistently occurred. Confocal microscopy imaging of these cell cultures stained for apoptosis and with cell type-specific markers confirmed that it was predominantly the SY cells that were dying. Microarray analysis demonstrated an intense microglia-mediated inflammatory response to B. burgdorferi including up-regulation in gene transcripts for TLR-2 and NF??. Surprisingly, a pathway that exhibited profound changes in regard to inflammatory signaling was triggering receptor expressed on myeloid cells-1 (TREM1). Significant transcript alterations in essential p53 pathway genes also occurred in SY cells cultured in the presence of microglia and B. burgdorferi, which indicated a shift from cell survival to preparation for apoptosis when compared to SY cells cultured in the presence of B. burgdorferi alone. Taken together, these findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect. If, as we hypothesized, neuronal apoptosis is the key pathogenic event in Lyme neuroborreliosis, then targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease. Author Summary Lyme disease, which is transmitted to humans through the bite of a tick, is currently the most frequently reported vector-borne illness in the northern hemisphere. Borrelia burgdorferi is the bacterium that causes Lyme disease and it is known to readily induce inflammation within a variety of infected tissues. Many of the neurological signs and symptoms that may affect patients with Lyme disease have been associated with B. burgdorferi-induced inflammation in the central nervous system (CNS).

In this report we investigated which of the primary cell types residing in the CNS might be functioning to create the inflammatory environment that, in addition to helping clear the pathogen, could simultaneously be harming nearby neurons.

We report findings that implicate microglia, a macrophage cell type in the CNS, as the key responders to infection with B. burgdorferi. We also present evidence indicating that this organism is not directly toxic to neurons; rather, a bystander effect is generated whereby the inflammatory surroundings created by microglia in response to B. burgdorferi may themselves be toxic to neuronal cells.

Viral infections often lead to inflammatory syndromes where arthralgias or
arthritis may represent a major manifestation.

Considerable evidence indicates that viruses may also be involved in
pathogenesis of autoimmune rheumatic diseases. Based on the hypothesis that
molecular interactions between the host genome and environmental factors are
critical for autoimmunity, endogenous retroviruses (ERV) are of particular
importance.

They belong to the larger family of retrotransposable elements that make up
as much as 40% of the human genome. ERV may have originated from exogenous
retroviruses that integrated into the genome and became trapped owing to
mutations of essential genes.

Human ERV have generally been found to be defective proviruses. They
represent a large reservoir of viral genes that may be activated by
mutations caused by radiation or chemicals, or recombination with exogenous
retroviruses.

While exogenous retroviruses are infectious, with a replication cycle that
requires integration of proviral DNA into host cell DNA, ERV are transmitted
genetically in a classical mendelian fashion through the germline as
proviral DNA. Expression of ERV can influence the outcome of infections in
different ways both beneficial and detrimental to the host. These include
provision of genes for recombination with exogenous viruses, interference
with virion assembly, blocking cellular receptors for viral entry, and
modulation of immune responses to exogenous viruses.

ERV may lead to autoimmunity directly, by encoding autoantigens, or
indirectly, by affecting the expression of genes regulating immune responses
and tolerance.

Research suggests that treating underlying infections and vitamin D receptor dysfunction may benefit and even reverse a number of autoimmune disorders.

For several decades researchers have known that mutations and other causes of dysfunction to the vitamin D receptor are routinely seen in a number of autoimmune disorders, particularly Graves? disease and multiple sclerosis. Because low vitamin D levels are seen in many of the autoimmune disorders that are more common in women, including Hashimoto?s thyroiditis, researchers have studied the vitamin D receptor, particularly the receptor expressed in the human cycling endometrium.

In a related line of study, researchers at the Autoimmunity Research Foundation report that scientists have identified a common intracellular bacterial infection as the cause of many chronic diseases, including those considered autoimmune as well as other idiopathic conditions, including chronic fatigue syndrome, myalgic encephalomyelitis, (CFS/ME), fibromyalgia, sarcoidosis and post-treatment Lyme disease syndrome (PTLDS). The role of vitamin D regulator dysfunction in perpetuating chronic bacterial infection has led to further research showing that correcting the infection and receptor dysregulation is key to treating autoimmune diseases.
The Vitamin D Receptor

To cause their intended effects, hormones and drugs attach to and activate protein receptors that reside on cells. For vitamin D to perform its intended functions, it must activate the vitamin D receptors found in the nucleus of cells located throughout the body. Besides its role in maintaining adequate blood levels of vitamin D, the vitamin D receptor controls expression of various antimicrobial peptides that offer natural protection against infection.

When the vitamin D receptor is dysregulated and no longer functioning properly, these peptides aren't produced and the innate immune response is compromised. This invariably leads to a chronic infection that contributes furhter to the vitamin D receptor dysregulation, which, in turn, causes the infection to persist. In addition, this dysregulation can prevent the normal breakdown of 1,25-OH vitamin D by metabolic enzymes. When present in high levels, 1,25-OH vitamin D binds the alpha and beta thyroid receptors, the glucocorticoid receptor and the androgen receptor, thereby displacing the hormones that normally react with these receptors and causing hormonal imbalances and endocrine disorders.

Amy Proal and her team at Georgetown University have found that if triiodothyronine (T3) is displaced, patients may develop thyroiditis. Because these receptors also express multiple types of antimicrobial peptides, production of these naturally occurring antibiotics declines even further, which allows infections to take hold. When levels of 1,25-OH remain elevated, conversion to the biologically active 25-OH vitamin D3 is impaired, and, consequently, 25-OH vitamin D3 levels decline. Because women have an extra vitamin D receptor in the endometrium, they?re more likely to have low production of antimicrobial peptides, higher bacterial loads (notably in pregnancy when levels of 1,25-OH vitamin D typically rise by 40 percent), and increased susceptibility to autoimmune disorders. This also explains why some autoimmune disorders such as systemic lupus tend to worsen or emerge during pregnancy and the postpartum period.
Linking Infection, Vitamin D, and Autoimmune Disease

The initial dysfunction in the vitamin D receptor leads to low levels of antimicrobial peptides and chronic infection. In addition, patients with vitamin D receptor dysfunction are susceptible to additional infections. The infections contribute to further vitamin D receptor dysregulation, causing low levels of vitamin D, reduced innate immune system function, and susceptibility to autoimmune disease.
Popular topics

Evidence from several studies indicates that a number of autoimmune diseases can be reversed by gradually restoring function of the vitamin D receptor. Studies show that vitamin D receptor function can be restored with the vitamin D receptor agonist drug olmesartan and long-term low doses of certain antibiotics. To date, diseases showing favorable responses to this treatment include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren?s syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter?s syndrome, type 1 and II diabetes mellitus, and uveitis. When using this type of treatment vitamin D supplementation needs to be limited in an effort to avoid vitamin D's contribution to dysfunction of nuclear receptors, which could lead to further imbalances in endocrine and immune function.
Sources

Proal, A; Albert, P; and TG Marshall. ?Dysregulation of the vitamin D nuclear receptor may contribute to the higher prevalence of some autoimmune diseases in women.? Annals of the New York Academy of Science, 2009 Sep; 1173: 252-259.

Nov. 9, 2012 — Australian scientists have confirmed a 'weak link' in the immune system -- identifying the exact conditions under which an infection can trigger an autoantibody response, a process not clearly understood until now.

We have known for many years that autoimmune diseases such as rheumatic fever and Guillain-Barré syndrome (where the body makes antibodies that attack the heart and peripheral nerves respectively) can occur after the body makes immune responses against certain infectious micro-organisms.

We have not been able to explain exactly how such examples of infection-driven autoimmunity occur, however, nor why our bodies seem unable to prevent them.

Our immune cells, such as the antibody-creating B cells, go through processes when they are first formed that ensure they are able to identify our own bodies, and therefore avoid self-attack. These processes are generally reliable as they take place in a steady, regulated way.

B cells go through a second and much more chaotic phase of development, however, when the body is fending off disease or infection. In order to cope with the immeasurable range of microbes in our environment, B cells have evolved the ability to mutate their antibody genes randomly until they produce one that sticks strongly to the invader. At that point, the 'successful' B cells proliferate and flood the system with these new antibodies.

This 'high affinity antibody' generation occurs very rapidly within specialised environments in the lymph system known as 'germinal centres'. Most of the time, germinal centres serve us well, helping us fight disease and build up a protective armory for the future.

Unfortunately, the urgency and speed at which B cells mutate within the germinal centre, as well as the random nature of the process, creates a unique problem. Sometimes the antibody created to fight the invader, or 'antigen', also happens to match 'self' and has the potential to cause autoimmune attack.

Dr Tyani Chan and Associate Professor Robert Brink from Sydney's Garvan Institute of Medical Research developed sophisticated mouse models to investigate when and how this happens. They demonstrated that when antigen is abundant and generally available throughout the body, rogue autoantibody-generating B cells are deleted and autoimmunity avoided. Conversely, when target antigen is located only in a tissue or organ remote from the germinal centre, B cells capable of reacting against both antigen and 'self' are able to escape the germinal centre and produce autoantibodies.

Their finding is published in the international journal Immunity.

"Essentially we've shown there's a big hole in self-tolerance when it comes to cross-reactive autoantibodies that can attack organ-specific targets," said Brink.

"Our finding explains a lot about how autoimmune conditions that target particular organs such as the heart or nervous system could develop after an infection. It also suggests that if you know enough about the disease and the molecular messaging systems involved, it may be possible in future to modulate the germinal centre response."

The team will continue to use their new mouse model to study the various molecular reactions involved in the progression of an autoimmune response.

Monash University researchers have found an important safety mechanism in the immune system that may malfunction in people with autoimmune diseases, such as Multiple Sclerosis, potentially paving the way for innovative treatments.

Published today in Immunity, the research, led by Head of the Monash Department of Immunology Professor Fabienne Mackay, described for the first time how the body manages marginal zone (MZ) B cells, which form a general first line of attack against germs, but are potentially harmful.

MZ B cells are integral to our defenses as they rapidly produce polyreactive antibodies that are capable of destroying a variety of pathogens. This first response gives the body time to put in place an immune reaction specific to the invading microbe.

However, MZ B cells have the potential to turn against the body. Some are capable of producing antibodies which attack healthy, rather than foreign, cells—known as an autoimmune response. Bacteria trigger MZ B cells irrespective of whether these cells are dangerous or benign, effectively placing anyone with a bacterial infection at risk of developing an autoimmune disease.

Professor Mackay's team has discovered the mechanism that regulates this response, ensuring that that the majority of infections do not result in the body attacking its own tissue.

"We found that while MZ B cells are rapidly activated, they have a very short life span. In fact, the very machinery which triggers a response leads to MZ B cells dying within 24 hours," Professor Mackay said.

"This means that in a healthy person, the potentially harmful immune cells are not active for long enough to cause in tissue damage. We now need to look at whether a malfunction in this safety feature is leading to some autoimmune diseases."

When MZ B cells are activated by bacteria, they express greater amounts of a protein known as TACI. When TACI binds to another protein as part of the immune response, this triggers the activation of the 'death machinery' inside MZ B cells. The detection of a pathogen sets of a chain reaction that both activates and then destroys MZ B cells.

Professor Mackay said this was an entirely new way of looking at the immune system.

"The research suggests that through evolution the immune system has not solely been vulnerable to infections but has learned to take advantage of pathogens to develop its own internal safety processes," Professor Mackay said.

"This says something important about our environment—pathogens are not always the enemy. They can also work hand in hand with our immune system to protect us against some immune diseases."